A feedback amplification loop between stem cells and their progeny promotes tissue regeneration and tumorigenesis.

Jun Chen,Na Xu,Huanwei Huang,Tao Cai,Rongwen Xi

doi:10.7554/elife.14330

Abstract

Homeostatic renewal of many adult tissues requires balanced self-renewal and differentiation of local stem cells, but the underlying mechanisms are poorly understood. Here we identified a novel feedback mechanism in controlling intestinal regeneration and tumorigenesis in Drosophila. Sox21a, a group B Sox protein, is preferentially expressed in the committed progenitor named enteroblast (EB) to promote enterocyte differentiation. In Sox21a mutants, EBs do not divide, but cannot differentiate properly and have increased expression of mitogens, which then act as paracrine signals to promote intestinal stem cell (ISC) proliferation. This leads to a feedback amplification loop for rapid production of differentiation-defective EBs and tumorigenesis. Notably, in normal intestine following damage, Sox21a is temporally downregulated in EBs to allow the activation of the ISC-EB amplification loop for epithelial repair. We propose that executing a feedback amplification loop between stem cells and their progeny could be a common mechanism underlying tissue regeneration and tumorigenesis.

Highlights

Adult stem cells have important roles in maintaining tissue and organ homeostasis by their prolonged ability to produce progenitor cells that differentiate into multiple types of mature cells
Its expression began to appear with age and at 4–5 days old, weak Sox21a expression appeared in Dl+ intestinal stem cell (ISC) and Notch-activated EBs that can be marked by a Notch activation reporter, Su(H)Gbe>green fluorescent protein (GFP) (NRE>GFP) (Figure 1B)
In each progenitor cell nest where the early EC still retained NRE>GFP expression, the early EC usually displayed a higher Sox21a expression level than the EB or the ISC in the same ISC-EB-early-EC cell nest (Figure 1D,F), suggesting that Sox21a is up-regulated in differentiating EBs

Summary

Introduction

Adult stem cells have important roles in maintaining tissue and organ homeostasis by their prolonged ability to produce progenitor cells that differentiate into multiple types of mature cells. The Drosophila midgut epithelium is constantly replenished by adult intestinal stem cells (ISCs) (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006), at a relatively slower pace. Signaling pathways that regulate mammalian ISC activity, such as Wnt, JAK/STAT, EGFR/Ras, Hippo, BMP and Notch, play important roles in regulating Drosophila ISC activity during normal homeostasis and/or stress conditions (reviewed by) (Biteau et al, 2011; Pasco et al, 2015). Enterocyte differentiation from EB requires high levels of Notch activation, and JAK/ STAT signaling activity is required for both enterocyte and enteroendocrine cell differentiation from

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Conclusion